The invention relates to a process for the manufacture of a pharmaceutical composition with modified release of active principle comprising a matrix.
xe2x80x9cPharmaceutical composition with modified release of active principlexe2x80x9d denotes the pharmaceutical compositions with accelerated, sustained and delayed release of active principle.
Various types of pharmaceutical compositions with modified release of active principle exist. Compositions comprising, on the one hand, uncoated granules constituting the dose of immediately available active principle and, on the other hand, coated granules providing for the modified release of active principle are particularly used.
Compositions comprising a matrix effect are also used.
The invention more particularly relates to the process for manufacturing the latter.
In this type of composition, the active principle is dispersed or coated in a solid system, known as a matrix. The release of the active principle from the matrix is achieved by contact of biological fluids with the said matrix. More specifically, biological fluids migrate through the matrix and dissolve the active principles and the latter are released by diffusion through the matrix which, simultaneously, modulates the release flow.
Hydrophilic matrices and hydrophobic matrices are distinguished.
In compositions comprising a hydrophilic matrix, the matrix is composed of an insoluble hydrophilic polymer, the concentration of which is between 25% and more than 50% of the weight of the composition, therefore high. This polymer is chosen from cellulose esters, carboxyvinyl esters, or acrylic or methacrylic esters. On contact with biological fluids, the matrix becomes hydrated and swells, forming a very dense network of polymers, through which polymers the soluble active principles diffuse. Furthermore, lipids, in particular glyceryl esters, as illustrated, for example, in the document FR-B-2,573,307, can be added in order to modulate the matrix swelling. In addition, these compositions include numerous adjuvants, often expensive adjuvants, at high concentrations, which greatly increases the cost of the composition.
These compositions are obtained by granulation and then compression of the mixture formed of the polymer, active principles and various adjuvants. These techniques often involve the use of organic solvents, which it is subsequently essential to recover in order to prevent them from dispersing into the atmosphere. In addition, traces of toxic solvents can remain in the final product, which traces necessarily have to be quantified.
In other words, the preparation of these compositions results in a high production cost, due to the cost of the various constituents of the composition, to their high proportions and to the technical constraints to be overcome.
In the compositions comprising a hydrophobic matrix, the matrix is composed of a lipid matrix agent of natural origin, for example beeswaxes, which is highly innocuous However, its composition varies from one batch to another and its stability over time is not very satisfactory.
As above, these compositions are generally obtained by granulation, by a wet or solvent route, and then compression, involving high proportions of each of the constituents.
The aim of the invention is thus to provide a novel process for the manufacture of a pharmaceutical composition with modified release of active principle by having the object of significantly decreasing the number and the proportions of each of the constituents as well as the number of operations, thus making it possible to obtain a formulation which is simple to employ and of low and reproducible cost.
To overcome this combination of problems, the invention provides a process for the manufacture of a pharmaceutical composition with modified release of active principle comprising at least one active principle, a lipid matrix agent composed of an ester of at least one fatty acid and of alcohol, and at least one adjuvant.
This process is characterized in that:
a powder composed of at least one component selected from the group comprising the active principle and the adjuvant is mixed, while heating and fluidizing, in order to obtain individual grains,
the said lipid matrix agent is liquefied separately under warm conditions,
the said powder is then coated under warm conditions by spraying the said lipid matrix agent over the individual grains, and, finally, the temperature of the combined product is lowered in order to allow the lipid matrix agent to solidify.
In other words, the invention lies in the employment of a specific process which makes it possible to decrease the number of adjuvants necessary for the preparation of the composition and thus to result in an extremely simple and low-cost formula.
In addition, the process of the invention does not require an evaporation phase or a drying phase, since it does not require a wet-route or solvent-route granulation step, thus making it possible to be freed from any risk due to the presence of toxic residues in the final product. Furthermore, it is no longer necessary to carry out the quantitative determination of the traces of solvents, an analysis which is very expensive.
According to the process of the invention, the praying conditions and thus the coating characteristics can be modified, in order to vary the release profile of the active principle, by varying several parameters, the adjustment characteristics of which remain simple.
Thus, the spraying air pressure can be increased in order to promote the formation of a homogeneous film of lipid matrix agent around the grains.
Advantageously, the rate of spraying of the lipid matrix agent can simultaneously be decreased.
In this case, an active principle release profile, that is to say a percentage of dissolution as a function of the time, is obtained which is very low, corresponding to a slow release of the active principle.
Conversely, the spraying air pressure can be decreased in order to promote the agglomeration of the grains with one another.
Advantageously, the rate of spraying of the lipid matrix agent can simultaneously be increased.
In this case, a release profile of the grains obtained is obtained which is very high, corresponding to a rapid release of the active principle.
In practice and according to the mass of powder employed, the value of the rate of spraying of the lipid matrix agent is from two to four times higher when it is desired to promote the agglomeration of the grains with one another than when it is desired to promote the formation of a homogeneous film around the grains.
On the other hand, the value of the spraying air pressure is from one to two times lower when it is desired to promote the agglomeration of the grains with one another than when it is desired to promote the formation of a homogeneous film around the grains.
According to the process of the invention, it is possible, after having determined a given active principle release profile, to vary the values of spraying air pressure and of spraying rate throughout the coating stage, making it possible to promote the formation of a homogeneous film around the grains or to promote the agglomeration of the grains.
Once the sequence of the duration of the spraying air pressure and of the spraying rate has been determined, the coating operation can be carried out continuously and automatically.
According to another characteristic of the invention, the temperature of the mixture of liquefied matrix agent and of spraying air must be greater by 35xc2x0 C. to 60xc2x0 C. than the melting temperature of the lipid matrix agent.
Likewise, the temperature of the fluidization air and that of the powder must be equal to the melting temperature of the lipid matrix agent, plus or minus 10xc2x0 C.
Furthermore, in order to obtain a mixture of individual grains, an air-operated fluidized bed device or a turbine device is used.
Furthermore, the lipid matrix agent can be sprayed by the air spray technique, that is to say liquid spraying under pressure in the presence of compressed air.
According to a first embodiment, use is made of a powder comprising the active principle and the adjuvant. In other words, after mixing and fluidizing the combined constituents of the powder, the lipid matrix agent is sprayed over the individual grains obtained.
When it is desired to package the product obtained in the form of a sachet or hard gelatin capsule, the spraying air pressure and the rate of spraying of the lipid matrix agent are adjusted to a value which makes it possible to promote the formation of a homogeneous film of lipid matrix agent around the grains.
When it is desired to obtain tablets, the coated grains are subjected to a compression stage.
In an entirely surprising way, it is found that, in the case where the individual grains are coated while promoting the formation of a homogenous film around the said grains, whereas they exhibit a very low release profile before compression, they exhibit, in contrast, a high release profile after compression.
Conversely, and in just as surprising a way, in the case where agglomeration of the individual grains is promoted, whereas the said grains exhibit a high release profile before compression, they exhibit, in contrast, a low release profile after compression.
As already said, it thus appears highly advantageous to vary the spraying conditions throughout the coating operation in order to more or less promote the release of the active principle.
According to another embodiment of the invention, a powder composed exclusively of the active principle is used.
According to this technique, the coated grains of active principle are mixed under cold conditions with uncoated adjuvants.
Likewise, a powder composed exclusively of adjuvant(s) can be used.
In this case, the coated adjuvant grains are mixed with the uncoated active principle.
As above, in order to obtain tablets, the mixture obtained is subjected to a compression stage.
The mixture obtained can be directly packaged in the form of sachets or hard gelatin capsules.
In order to avoid adhesion of the coated grains obtained, whether in the case where all the grains are treated or whether in the case where only a portion of the grains is treated, a stage of lubrication of the grains is inserted between the coating stage and the stage of putting into a pharmaceutical form.
Furthermore, in order to obtain greater stability of the pharmaceutical composition, that is to say in order to minimize modifications relating to the release of the active principle or principles over time, the granules or tablets obtained can be subjected to a maturing stage in an oven, for at least 8 hours, at a temperature of between 45 and 60xc2x0 C., advantageously 55xc2x0 C.
In order to solve the problem of obtaining a composition in which the proportions of constituents are low, use is made of an amount of matrix agent representing, by weight, from 1 to 15% of the final composition, advantageously from 2 to 5%.
Success is not achieved in obtaining an even coating for a value of lipid matrix agent of less than 1%.
The process becomes much less advantageous economically for a value greater than 15%.
These proportions are thus very low with respect to those used in the prior art, in particular in the abovementioned document FR-B-2,573,307, in which the proportions disclosed are much greater than 15% by weight of the final composition, generally 30%.
According to a first embodiment of the invention, use is made, as lipid matrix agent, of an ester of behenic acid and of alcohol.
The alcohol is advantageously chosen from the group comprising glycerol, polyglycerol, propylene glycol, propylene glycol in combination with ethylene oxide and polyethylene glycol.
These matrix agents exhibit the advantage of having a melting point of greater than 50xc2x0 C., which prevents them from disintegrating at the compression temperature. Furthermore, this melting point is greater than the internal temperature of the human body (37xc2x0 C.), which allows the lipid agent to have a more pronounced matrix behaviour.
In addition, the spraying of an ester of fatty acid and of alcohol as lipid matrix agent makes it possible, in addition to the fact of accelerating or of slowing down the release of the active principle, furthermore to mask the taste of the starting material. This is truly advantageous insofar as none of the current masking techniques makes it possible to mask the taste of the starting materials without excessively slowing down the release of the active principle.
Use is advantageously made of the ester of behenic acid and of glycerol exhibiting a melting point of between 69 and 74xc2x0 C. and therefore much greater than 50xc2x0 C. This ester results from the direct esterification of behenic acid with glycerol, to result in a mixture of glyceryl mono-, di- and tribehenate.
According to another embodiment, the lipid matrix agent is an ester of palmitic/stearic acid and of alcohol.
According to another characteristic of the invention, the adjuvant is chosen from hydrophobic diluting agents, hydrophilic diluting agents, binding agents or lubricating agents, alone or as a mixture.
In an advantageous embodiment, the hydrophobic diluting agent is dicalcium phosphate and the hydrophilic diluting agent is lactose.
Dicalcium phosphate exhibits the advantage of being very low in cost, which contributes to reducing the final cost of the composition.
Furthermore, the use of lactose as hydrophilic diluting agent makes it possible to adjust the hydrophilic/lipophilic balance necessary for the release of active principle.
In order to promote the compressibility of the grains during the manufacture of tablets, use is made of polyvinylpyrrolidone as binding agent, which makes it possible to decrease the compressive forces of the pharmaceutical composition.
In order to avoid the adhesion of the powder to the walls of the machine during the compressing operation, the pharmaceutical composition comprises a lubricating agent chosen within the group comprising magnesium stearate and silicone-treated talc, alone or in combination.
The silicone-treated talc is advantageously composed of 80% talc and 20% silicone oil.
The invention also relates to the composition obtained by the process described above.
Nevertheless, this modified-release pharma-eutical composition can be obtained by other processes and in particular that of wet granulation, in which use is made of water as granulation solvent.
A wet granulation of the products constituting the powder is thus carried out in a known way in order to succeed in obtaining granules, which are either introduced into capsules or agglomerated by pressing in order to obtain tablets.